Although lung transplant rejection has traditionally been thought to occur as a result of host adaptive immune[unreadable] responses to alloantigens present in the donor lung, the lung is unique among transplanted organs in its[unreadable] constant exposures to environmental stimuli and in its intrinsic innate host defenses. Toll-like receptors[unreadable] (TLRs) expressed on pulmonary cells provide the first line of host defense against foreign pathogens and[unreadable] environmental challenges. Our preliminary results demonstrate that polymorphisms of TLR4, which diminish[unreadable] innate responsiveness, also diminish susceptibility to the development of acute rejection. These TLR4[unreadable] polymorphisms also lead to a reduction in the severity of bronchiolitis obliterans syndrome (BOS), a condition[unreadable] of chronic allograft rejection associated with airflow obstruction and airway obliteration. Based on these[unreadable] observations we hypothesize that activation of innate immunity through TLRs in the transplanted lung[unreadable] promotes the adaptive alloimmune response that leads to acute rejection and BOS. Further support for this[unreadable] hypothesis is provided by the observation that aerosolized challenge with lipopolysaccharide (IPS), a[unreadable] prototypic trigger of innate immunity, leads to the development of pathological lesions of acute rejection and[unreadable] lymphocytic bronchiolitis in mice that have undergone allogenic bone marrow transplant (BMT). In this[unreadable] project we will specifically test the hypothesis that polymorphisms in human TLRs and in related genes[unreadable] transcriptionally activated by LPS regulate the innate response to lung transplant and determine susceptibility[unreadable] to acute rejection and BOS in the following aims: Aim 1 will identify polymorphic variants in TLRs and related[unreadable] innate molecules. Aim 2 will identify polymorphic variations in human candidate genes derived[unreadable] experimentally from differential gene expression studies of LPS induced lung rejection in mice. Aim 3 will[unreadable] genotype 800 lung transplant recipients and their donors for polymorphic variants in candidate genes. Aim 4[unreadable] will determine if allelic variants in candidate genes among lung transplant recipients or their donors[unreadable] significantly alters the risk for acute rejection or BOS. Completion of these aims will significantly increase our[unreadable] understanding of innate immune regulation of lung transplant rejection and will provide a basis for the[unreadable] development of innovative therapeutic strategies to prevent lung transplant rejection. This project will interact[unreadable] with all cores and include investigations of the TLRs (activated by hyaluronic acid, Project 3) and surfactant[unreadable] proteins A and D (Project 1) in regulating the development of lung transplant rejection.